Early Translational IV
$1 801 237
For patients with end stage lung disease currently the only treatment option is lung transplantation and there are not enough lungs available for everyone who needs them. In addition, rejection after lung transplantation is very common and the medicines taken to suppress the immune system often result in serious infections. We are proposing to use patient specific induced pluripotent stem cells and a novel bioengineering approach to make patient specific lung tissues for patients with poor lung function. The goal is to transplant these patient specific lung tissues into patients with lung diseases to improve their breathing and prevent the need for a lung transplant from an unmatched lung. We will make patient specific lung tissues as a potential development candidate and perform a preclinical test of these lungs in a small animal transplant model.
Statement of Benefit to California:
There are millions of people in the USA who suffer from lung diseases. The lungs have tremendous reserve, so that it is not until many years after lung injury that respiratory symptoms become manifest. California, the most populous state, is also the state with the largest number of people 65 years of age and over (3.6 million people in the year 2000) and therefore the prevalence of severe lung diseases in the USA is highest in California with a conservative estimate of over 100,000 cases. Of these, the worst cases develop end stage lung disease and either succumb to their disease or undergo a lung transplant. There were 190 lung transplants in California in 2012 and many more patients on the waiting list. Yet, most of the patients who were fortunate enough to receive a lung transplant will not be disease free, as 50% of them will develop rejection of their lung and they are all at risk for severe infections from the medications that reduce the immune system to try to prevent rejection. We are proposing to develop small lung organs from patient specific induced pluripotent stem cells that could be transplanted into patients to help them breathe without any risk of rejection and therefore without the need for medications to reduce the immune system. This would therefore be a ground breaking new treatment for patients with severe lung diseases and will greatly benefit the people of California with lung diseases.
This development candidate feasibility (DCF) application focuses upon developing a tissue replacement treatment for patients with end stage lung disease. End stage lung disease currently has only one treatment option: lung transplantation. However, there are not enough lungs available for all patients who need them, and immune rejection is very common. The applicant proposes to develop an autologous, engraftable, functional lung organoid generated by seeding induced pluripotent stem cell (iPSC)-derived lung cells on a scaffold. The applicant intends to develop and validate a reproducible method for generating the cellular components of the development candidate. Reproducible methods to manufacture three-dimensional alveolar structures seeded with cells will be established. The team plans to develop assays to assess gas exchange function of the organoids, and demonstrate safety and efficacy of the alveolar structures in an animal model. Objective & Milestones - Reviewers stated that key aspects of the cell biology and tissue engineering components are better suited to a basic research program and are premature for translation. - Reviewers felt the proposed milestones were set on an unrealistic timeline and did not follow an adequate development plan for a cellular combination product. Rationale & Significance - Alternative treatments for end stage lung disease are needed. Currently the only treatment option, lung transplantation, is hampered by both a shortage of donor organs and frequent immune rejection. - Reviewers appreciated the applicant’s proposed approach; however, there is substantial, more advanced competition in this regard using the decellularized and recellularization approach. The panel estimated that the current project would take several more years to complete than proposed which would limit its potential impact. Feasibility & Design - Preliminary data were inadequate to support feasibility for generating the complex proposed development candidate. - The panel expressed skepticism over the potential success of a non-vascularized organoid given that successful lung function and survival is tightly linked to the complex blood supply of the organ. They felt a pro-angiogenic factor was unlikely to accurately replicate this complexity. - Reviewers were not convinced that an engineered construct with this degree of complexity could be reproducibly generated from autologous iPSC. - The basic scaffold design requires further development. For example, it is unclear how consistently the alveolar scaffold can achieve the intended geometry, and there are no data yet on functional seeding of the scaffold. Qualification of the PI (Co-PI, Partner PI, if applicable) & Research Team - The assembled team is largely appropriate, but would benefit from the involvement of thoracic transplant surgeons. Collaborations, Assets, Resources, & Environment - The reviewers did not highlight any relevant concerns under this criterion. Responsiveness to the RFA - The application is responsive to the RFA and the target disease is clearly identified.